Fetal-maternal genetic interactions and the effects of maternal age at first pregnancy on breast cancer susceptibility

女性首次足月妊娠的年龄对其一生患乳腺癌的风险有影响：20岁以下，有保护作用；到了25岁，在保护作用开始之前，分娩前后的风险就会增加；25岁后，保护作用减弱。35岁生育的女性比未生育的女性患乳腺癌的风险更高。早期妊娠诱导的基因组表达谱在绝经后的乳腺组织中仍可识别，包括转录因子和编码凋亡和DNA修复相关蛋白的基因。然而，胎儿驱动的胎盘生长因子对怀孕期间母体乳腺分化的影响，或调节它们的遗传相互作用，知之甚少。目前尚不清楚胎盘生长因子水平是否随母亲年龄的不同而不同。印迹基因编码了约95种胎盘和胎儿生长调节因子。本项目将检测胎盘组织中印迹基因的表达水平与妊娠不同阶段母体血清中内分泌生长激素水平和胰岛素信号标志物的关系，研究对象为首次妊娠的不同年龄组妇女。胎盘组织和匹配的母体血清样本可从BabyBioBank获得。胎盘样品将使用焦磷酸测序和靶向RNA测序检测印迹DNA甲基化和表达。匹配的母体血清样本将通过质谱分析胎盘印迹基因表达与血清生长因子和激素水平的相关性。这些数据将与使用METABRICproject等公开数据集的乳腺癌患者正常和肿瘤组织中的基因表达谱进行比较。来自RUH乳腺癌诊所的样本将用于验证分析中确定的选定基因的表达。该结果将为研究母胎基因回路及其对乳腺分化的影响提供有价值的信息。未来的研究将检验这些基因回路是否具有预防乳腺癌的作用。当妇女倾向于推迟生育时，这是一个特别相关的项目：1970年，第一次怀孕的平均年龄为21.4岁；2013年是30.3年。2002-2004年和2011-2013年期间，女性乳腺癌发病率（年龄标准化）增加了6%。随着女性推迟生育，患乳腺癌的风险将增加，因此，通过改变乳房基因表达谱来了解胎盘发育是否会影响风险的方法，将改善孕产妇的健康结果和终身健康。该项目属于MRC战略研究重点的“改善健康结果”和“了解终身健康的遗传学方法”。孕妇是公共健康筛查项目的优先对象，以确保改善下一代的健康状况。该项目提供跨学科研究培训，包括实验设计和统计学，以便利用现有的胎盘和母体血清样本进行人口研究。它与MRC DTP的目标一致，优先考虑交叉技能领域，如定量技能和体内科学。监督团队的目标是支持GW4与合作机构之间的合作，包括早期职业研究人员

A woman's age at first full-term pregnancy impacts on her life-long breast cancer risk: below the age of 20, there is aprotective effect; by 25, there is an increase in risk around childbirth before the protective effect starts; after 25 theprotective effect is reduced. Women who give birth at 35 have a higher breast cancer risk than nulliparous women.Early pregnancy induces a genomic expression profile that is still identifiable in post-menopausal breast tissue, andincludes transcription factors and genes encoding apoptosis- and DNA repair-related proteins. However, little isknown about the impact of fetus-driven placental growth factors on maternal mammary gland differentiation duringpregnancy, or the genetic interactions that regulate them. It is not known whether placental growth factor levels differwith maternal age.About 95 placental and fetal growth regulating factors are encoded by imprinted genes. This project will examineexpression levels of imprinted genes in placental tissue relative to endocrine growth hormone levels and insulinsignalling markers in maternal serum during different stages of pregnancy, in women of different age groupsexperiencing a first pregnancy.Placental tissue and matched maternal serum samples are available from BabyBioBank. Placenta samples will beassayed for imprinted DNA methylation and expression using pyrosequencing assays and targeted RNA sequencing.Matched maternal serum samples will be analysed by mass spectrometry to correlate placental imprinted geneexpression with serum growth factors and hormone levels. These data will be compared to gene expression profilesin normal and tumour tissues of breast cancer patients using publicly available data sets such as the METABRICproject. Samples from the breast cancer clinic at RUH will be used to validate expression of selected genes identifiedin the analysis.The results will provide valuable information on fetal-maternal gene circuits and their influence on m ammary glanddifferentiation. Future studies will examine whether these gene circuits confer protection against breast cancer. Thisis a particularly pertinent project when women are tending to delay childbearing: in 1970, the average age of firstpregnancy was 21.4 years; in 2013 it was 30.3 years. Between 2002-2004 and 2011-2013, female breast cancerincidence rates (age standardised) have increased by 6%. As women delay having children the risk for breast cancerwill increase, therefore this approach to understanding whether placental development influences risk by alteringmammary gene expression profiles would lead to improved maternal health outcome and lifelong health.The project falls within the MRC strategic research priorities of "improved health outcome" and "genetics approach tounderstand lifelong health". Pregnant women are a priority in public health screening programs to ensure improvedhealth outcome for the next generation.The project provides cross-disciplinary research training, including in experimental design and statistics to carry out apopulation study using the available placenta and maternal serum samples. It aligns with MRC DTP goals prioritisingcross-cutting skills areas such as quantitative skills and in vivo science. The supervising team matches the aim tosupport collaboration across the GW4 the partner institutions, and includes early career researchers